ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: oHypersensitivity Reactions [see Warnings and Precautions (5.1)]. oHypersensitivity Reactions [see Warnings and Precautions (5.1)]. Most common adverse reactions (at least 2% of patients treated with ZAVZPRET and greater than placebo) were taste disorders, nausea, nasal discomfort, and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety of ZAVZPRET for the acute treatment of migraine in adults has been evaluated in two randomized, double-blind, placebo-controlled trials (Study and Study 2) in patients with migraine who received one 10 mg dose of ZAVZPRET nasal spray (N=1023) or placebo (N=1056) [see Clinical Studies (14)]. Approximately 83% were female, 81% were White, 20% were Hispanic or Latino, and 15% were Black. The mean age at study entry was 41 years (range 18-79 years of age).Adverse reactions in Study and are shown in Table 1.Table 1: Adverse Reactions Occurring in At Least 2% of Patients Treated with ZAVZPRET and at Frequency Greater than Placebo in Study and 2Adverse ReactionZAVZPRETN=1023%PlaceboN=1056%Taste DisordersTaste disorders includes dysgeusia and ageusia 184Nausea41Nasal Discomfort31Vomiting2<1Hypersensitivity, including facial swelling and urticaria, occurred in less than 1% of patients treated with ZAVZPRET [see Contraindications (4) and Warnings and Precautions (5.1)]. Long-term safety was assessed in an open-label extension study. That study evaluated 603 patients, dosing intermittently for up to one year, including 360 patients who were exposed to ZAVZPRET 10 mg for at least months, and 298 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Zavegepant is calcitonin gene-related peptide (CGRP) receptor antagonist.. 12.2Pharmacodynamics. The relationship between pharmacodynamic activity and the mechanism by which zavegepant exerts its clinical effects is unknown.No clinically relevant differences in resting blood pressure were observed when zavegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.Cardiac ElectrophysiologyAt dose up to times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.. 12.3Pharmacokinetics. Absorption Peak plasma concentration of zavegepant was observed at approximately 30 minutes after single 10 mg dose of the nasal spray. After nasal spray administration of zavegepant, the absolute bioavailability is approximately 5%. Zavegepant given as single dose of the nasal spray displays slightly less than dose-proportional pharmacokinetics up to 40 mg (approximately times the recommended dosage of 10 mg). Following once daily dosing of ZAVZPRET for 14 days there was no evidence of zavegepant accumulation. Distribution The mean apparent volume of distribution of intranasal zavegepant is approximately 1774 L. Plasma protein binding of zavegepant is approximately 90%.EliminationMetabolismZavegepant is primarily metabolized by CYP3A4 and to lesser extent by CYP2D6, in vitro. After single IV dose of mg [14C]-zavegepant, unchanged zavegepant was the most prevalent (approximately 90%) circulating component in the human plasma. No major metabolites (i.e., greater than 10%) of zavegepant were detected in plasma.ExcretionThe effective half-life of zavegepant following 10 mg dose of the nasal spray is 6.55 hours. The mean apparent clearance of intranasal zavegepant is 266 L/h. Zavegepant is excreted mostly via the biliary/fecal route, while the renal route is minor route of elimination. Following single intravenous dose of mg [14C]-zavegepant to healthy male subjects, approximately 80% and 11% of the dose was recovered as unchanged zavegepant in feces and urine, respectively.Specific PopulationsPatients with Hepatic ImpairmentIn dedicated clinical study comparing the pharmacokinetics of zavegepant in subjects with moderate hepatic impairment (Child-Pugh B) to that of normal subjects (matched healthy controls), zavegepant Cmax was 16% higher and AUC was 1.9-fold higher in patients with moderate hepatic impairment. These changes in exposures are not expected to be clinically significant, based on clinical safety experience and minimal accumulation of drug exposures. The impact of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of zavegepant was not studied [see Use in Specific Populations (8.6)]. Patients with Renal ImpairmentThe renal route plays minor role in the clearance of zavegepant. No clinically significant effect on the pharmacokinetics of zavegepant is expected in subjects with estimated creatinine clearance (CLcr) 30 mL/min or greater. In patients with CLcr 15 to 29 mL/min, accumulation of uremic solutes can cause an increase in zavegepant exposures by inhibiting OATP transporters. Zavegepant has not been studied in patients with CLcr less than 15 mL/min [see Use in Specific Populations (8.7)].Other Specific PopulationsAge, sex, race, ethnicity, and body weight did not show clinically significant effects on the pharmacokinetics of zavegepant. Drug Interaction StudiesIn Vitro StudiesEnzymes Zavegepant is substrate of CYP3A4 and to lesser extent CYP2D6. Zavegepant is not an inducer of CYP1A2, 2B6, or 3A4, or an inhibitor of CYP1A2, CYP2C9, 2C19, 2B6, 2D6, 2C8, and 3A4 at clinically relevant concentrations.Transporters Zavegepant is substrate for OATP1B3 and NTCP (see In Vivo studies).Zavegepant is also substrate for the transporters P-gp, MATE1, and MATE2-K. Considering the minor contribution of the renal pathway in the clearance of zavegepant, coadministration of zavegepant with inhibitors of P-gp, MATE1, and MATE2-K inhibitors is not expected to result in clinically significant effect on zavegepant pharmacokinetics. Zavegepant is not substrate for BCRP, OATP1B1, OAT1, OAT3, OCT2, BSEP, MRP2, MRP3, and MRP4. Zavegepant is an inhibitor of OCT2, MATE1, and MATE2-K, but drug interactions for ZAVZPRET are not expected at clinically relevant concentrations. Zavegepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, OATP1B1, and OATP1B3. In Vivo StudiesCYP3A4 Inhibitors Concomitant administration of single dose of 10 mg ZAVZPRET with itraconazole (a strong CYP3A4 and P-gp inhibitor), at steady state did not result in clinically relevant effect on the exposures of zavegepant. OATP1B3 or NTCP InhibitorsConcomitant administration of single oral dose of 100 mg zavegepant with rifampin (an OATP1B3, NTCP inhibitor and strong CYP3A inducer), at steady state resulted in increased zavegepant exposure (AUC by 2.3-fold and Cmax by 2.2-fold). The observed change in zavegepant exposures is composite effect of inhibition of OATP1B3 and NTCP transporters as well as induction of CYP3A enzymes. Concomitant administration of ZAVZPRET with inhibitors of OATP1B3 or NTCP transporters may result in significant increase in zavegepant exposure [see Drug Interactions (7.1)].OATP1B3 or NTCP Inducers Concomitant administration of ZAVZPRET with inducers of OATP1B3 or NTCP transporters has not been studied. However, since zavegepant is substrate of OATP1B3 and NTCP, concomitant administration with inducers of these transporters may result in decreased zavegepant exposure [see Drug Interactions (7.2)]. Intranasal DecongestantsThe effect of concomitant intranasal decongestants on the pharmacokinetics of zavegepant nasal spray has not been evaluated. Concomitant administration of intranasal decongestants may decrease the systemic exposure of zavegepant and potentially the efficacy of zavegepant [see Drug Interactions (7.3)]. Other DrugsNo significant pharmacokinetic interactions were observed when zavegepant was concomitantly administered with oral contraceptives (ethinyl estradiol) or sumatriptan [see Clinical Pharmacology (12.2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of ZAVZPRET for the acute treatment of migraine with or without aura in adults was demonstrated in two randomized, double-blind, placebo-controlled trials (Study and Study 2). In both studies, patients were instructed to treat migraine of moderate to severe headache pain intensity. Rescue medication (i.e., NSAIDs, acetaminophen, and/or an antiemetic) was allowed hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment. In Study and Study 2, 13.4% and 13.6% of patients were taking preventive medications for migraine at baseline, respectively. None of the patients were on concomitant preventive medication that act on the CGRP pathway.In Study (NCT04571060), patients were randomized to receive single dose of ZAVZPRET 10 mg (N=623) or placebo (N=646). Efficacy was demonstrated with ZAVZPRET 10 mg by an effect on the coprimary endpoints of pain freedom and most bothersome symptom (MBS) freedom at hours after single dose, compared to placebo. Pain freedom was defined as reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). The most common MBS reported before dosing was photophobia (55%), followed by nausea (28%), and phonophobia (16%).In Study 1, the percentage of patients achieving headache pain freedom and MBS freedom hours after single dose was statistically significantly greater in patients who received ZAVZPRET compared to those who received placebo (Table 2).Table 2: Efficacy Endpoints in Study 1ZAVZPRET10 mgPlaceboPain Free at hours n/Nn=number of responders/N=number of patients in that treatment group 147/62396/646 Responders23.614.9 Difference from placebo (%)8.8 p-value<0.001MBSMBS most bothersome symptoms of photophobia, phonophobia, or nausea. Free at hours n/N 247/623201/646 Responders39.631.1 Difference from placebo (%)8.7 p-value0.001Figures and present the percentage of patients achieving migraine pain freedom and MBS freedom within hours following treatment in Study 1.Figure 1: Percentage of Patients Achieving Pain Freedom within Hours in Study 1Figure 2: Percentage of Patients Achieving MBS Freedom within Hours in Study 1In Study 1, statistically significant effects of ZAVZPRET compared to placebo were demonstrated for the additional efficacy endpoints of pain relief at hours post-dose, return to normal function at hours post-dose, sustained pain freedom from to 48 hours post-dose (Table 3), and phonophobia and photophobia freedom at hours post-dose. Pain relief was defined as reduction in migraine pain from moderate or severe severity to mild or none. The measurement of the percentage of patients reporting normal function at two hours after dosing was derived from single text questionnaire, asking patients to select one response on 4-point scale: normal function, mild impairment, severe impairment, or required bedrest.Table 3: Additional Efficacy Endpoints in Study 1ZAVZPRET10 mgPlaceboPain Relief at hours n/Nn=number of responders/N=number of patients in that treatment group 366/623321/646 Responders58.749.7 Difference from placebo (%)9.0 p-value0.001Percentage of Patients Reporting Normal Function at hoursIncludes patients with functional disability at time of dosing, according to the functional disability scale. n/N 204/570152/593 Responders35.825.6 Difference from placebo (%)10.2 p-value<0.001Sustained Pain Freedom from to 48 hours n/N 77/62356/646 Responders12.48.7 Difference from placebo (%)3.7 p-value0.031The incidence of photophobia and phonophobia was reduced following administration of ZAVZPRET 10 mg as compared to placebo.In Study (NCT03872453), patients were randomized to receive single dose of ZAVZPRET 10 mg (n=391) or placebo (n=401). In Study 2, statistically significant efficacy was demonstrated with ZAVZPRET 10 mg by an effect on the coprimary endpoints of pain freedom and most bothersome symptom (MBS) freedom at hours after single dose, compared to placebo. Pain freedom was observed in 22.5% of patients receiving ZAVZPRET and 15.5% of patients receiving placebo (p-value 0.011). MBS freedom was observed in 41.9% of patients receiving ZAVZPRET and 33.7% of patients receiving placebo (p-value 0.016). The most common MBS reported before dosing was photophobia (53%), followed by nausea (31%), and phonophobia (15%).Table 4: Efficacy Endpoints in Study 2ZAVZPRET10 mgPlaceboPain Free at hours n/Nn=number of responders/N=number of patients in that treatment group 88/39162/401 Responders22.515.5 Difference from placebo (%)7.0 p-value0.011MBSMBS most bothersome symptoms of photophobia, phonophobia, or nausea. Free at hours n/N 164/391135/401 Responders41.933.7 Difference from placebo (%)8.3 p-value0.016Figure 3: Percentage of Patients Achieving Pain Freedom within Hours in Study 2Figure 4: Percentage of Patients Achieving MBS Freedom within Hours in Study 2. Figure 1. Figure 2. Figure 3. Figure 4.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oAvoid use with drugs that inhibit OATP1B3 or NTCP transporters. (7.1)oAvoid use with drugs that induce OATP1B3 or NTCP transporters. (7.2)oAvoid use of intranasal decongestants; if unavoidable, administer intranasal decongestants at least hour after ZAVZPRET administration. (7.3). oAvoid use with drugs that inhibit OATP1B3 or NTCP transporters. (7.1). oAvoid use with drugs that induce OATP1B3 or NTCP transporters. (7.2). oAvoid use of intranasal decongestants; if unavoidable, administer intranasal decongestants at least hour after ZAVZPRET administration. (7.3). 7.1OATP1B3 or NTCP Inhibitors. Concomitant administration of ZAVZPRET with inhibitors of the organic anion transporting polypeptide 1B3 (OATP1B3) or sodium taurocholate co-transporting polypeptide (NTCP) transporters may result in significant increase in zavegepant exposure. Avoid concomitant administration of ZAVZPRET with drugs that inhibit OATP1B3 or NTCP transporters [see Clinical Pharmacology (12.3)].. 7.2OATP1B3 or NTCP Inducers Concomitant administration of ZAVZPRET with inducers of OATP1B3 or NTCP transporters may result in decrease in zavegepant exposure. Avoid concomitant administration of ZAVZPRET with drugs that induce OATP1B3 or NTCP transporters [see Clinical Pharmacology (12.3)].. 7.3Intranasal Decongestants Concomitant administration of ZAVZPRET with intranasal decongestants may decrease the absorption of zavegepant. Avoid concomitant administration of intranasal decongestants with ZAVZPRET. When concomitant use is unavoidable, intranasal decongestants should be administered at least hour after ZAVZPRET administration [see Clinical Pharmacology (12.3)].

INSTRUCTIONS FOR USE SECTION.

Instructions for Use INSTRUCTIONS FOR USEZAVZPRET [zav-spret](zavegepant) nasal sprayFor Nasal Use OnlyThis Instructions for Use contains information on how to give single dose (10 mg) with ZAVZPRET nasal sprayOne (1) device delivers single dose of ZAVZPRET. The device provides spray that should be delivered into nostril.ZAVZPRET Device PartsImportant Information You Need to Know Before Dosing with ZAVZPREToFor nasal use only (spray into nose).oDo not spray in the eyes.oKeep ZAVZPRET and all medicines out of reach of children.oDo not use if the expiration (EXP) date has passed. Throw away the expired device in the trash if the expiration (EXP) date has passed.oDo not remove the device from its blister packaging until you are ready to use it.oDo not test spray, prime, or press the plunger before dosing. Each device is single use and can only be used time. If you press the plunger before dosing, the spray will be lost, and the device will no longer function.oDo not try to spray (dose) into more than nostril. dose is spray into nostril. oDo not use more than dose in 24-hour period. Only dose can be used per day. oDo not use more than doses per month. maximum of doses can be used per month. Storage InformationoThe device should be stored at room temperature between 68F to 77F (20C to 25C).oDo not freeze.oKeep the device in the sealed blister package until time of use.oKeep ZAVZPRET and all medicines out of reach of children.Preparing to Dose with ZAVZPRET Nasal Spray1Gently Blow Your Nose1.1Before using ZAVZPRET, blow your nose to clear your nostrils (see Figure B). This can be done while sitting or standing.2Remove Blister from the Carton2.1Remove blister containing device from the carton (see Figure C).3Check Expiration Date on the Blister3.1Check the expiration date on the blister containing device (see Figure D).Do not use if the expiration date has passed. Throw away the expired device in the trash if the expiration date has passed.4Remove Device from Blister4.1Peel open the blister seal from the corner and remove it completely (see Figure E).4.2Carefully remove the device from the plastic tray.Dosing with ZAVZPRET Nasal Spray5Check Expiration Date on the Device5.1Check the expiration date on the device (see Figure F). Do not use if the expiration date has passed. Throw away the expired device in the trash if the expiration date has passed.6Grip the Device6.1Hold the device upright with your thumb on the bottom of the plunger and two fingers on either side of the nozzle (see Figure G).Do not press the plunger yet. If you press the plunger now, the medicine will spray and be wasted.Dosing with ZAVZPRET Nasal Spray (Continued)7Close Nostril7.1With your free hand, gently press nostril to close it (see Figure H).7.2Continue breathing normally through your mouth.8Insert Spray Nozzle Into Open Nostril8.1Insert the nozzle into the open nostril as much as you comfortably can (see Figure I).9Deliver the Dose by Spraying Into Nostril and Breathing In9.1Keep your head level and upright and close your mouth.Do not tilt your head.Do not lay down while delivering the dose.9.2Slowly breathe in through your nose as you firmly press the plunger up with your thumb to release the spray (see Figure J).Important: Hold the nozzle firmly in your nose as you deliver the dose. Do not let the nozzle come out when pressing the plunger.Spray only time into nostril.10Remove the Device and Keep Your Head Level for 20 Seconds10.1Remove the device from your nostril and your finger from your other nostril.10.2While keeping your head level and upright, gently breathe in through your nose and out through your mouth for 10 to 20 seconds (see Figure K).If you feel drip from your nose, gently sniff so you do not lose any of your dose.Throwing away (Disposing of) Device11Throw Away Used Device11.1Throw away the used device into trash (see Figure L)You have received your full dose, if you have: Used deviceGiven spray into nostrilAdditional InformationFor more information on ZAVZPRET (zavegepant), visit www.zavzpret.com or call 1-800-438-1985.This Instructions for Use has been approved by the U.S. Food and Drug Administration Approved: 3/2023LAB-1546-1.0. oFor nasal use only (spray into nose).. oDo not spray in the eyes.. oKeep ZAVZPRET and all medicines out of reach of children.. oDo not use if the expiration (EXP) date has passed. Throw away the expired device in the trash if the expiration (EXP) date has passed.. oDo not remove the device from its blister packaging until you are ready to use it.. oDo not test spray, prime, or press the plunger before dosing. Each device is single use and can only be used time. If you press the plunger before dosing, the spray will be lost, and the device will no longer function.. oDo not try to spray (dose) into more than nostril. dose is spray into nostril. oDo not use more than dose in 24-hour period. Only dose can be used per day. oDo not use more than doses per month. maximum of doses can be used per month. oThe device should be stored at room temperature between 68F to 77F (20C to 25C).. oDo not freeze.. oKeep the device in the sealed blister package until time of use.. oKeep ZAVZPRET and all medicines out of reach of children.. Used device. Given spray into nostril. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Logo.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Absorption Peak plasma concentration of zavegepant was observed at approximately 30 minutes after single 10 mg dose of the nasal spray. After nasal spray administration of zavegepant, the absolute bioavailability is approximately 5%. Zavegepant given as single dose of the nasal spray displays slightly less than dose-proportional pharmacokinetics up to 40 mg (approximately times the recommended dosage of 10 mg). Following once daily dosing of ZAVZPRET for 14 days there was no evidence of zavegepant accumulation. Distribution The mean apparent volume of distribution of intranasal zavegepant is approximately 1774 L. Plasma protein binding of zavegepant is approximately 90%.EliminationMetabolismZavegepant is primarily metabolized by CYP3A4 and to lesser extent by CYP2D6, in vitro. After single IV dose of mg [14C]-zavegepant, unchanged zavegepant was the most prevalent (approximately 90%) circulating component in the human plasma. No major metabolites (i.e., greater than 10%) of zavegepant were detected in plasma.ExcretionThe effective half-life of zavegepant following 10 mg dose of the nasal spray is 6.55 hours. The mean apparent clearance of intranasal zavegepant is 266 L/h. Zavegepant is excreted mostly via the biliary/fecal route, while the renal route is minor route of elimination. Following single intravenous dose of mg [14C]-zavegepant to healthy male subjects, approximately 80% and 11% of the dose was recovered as unchanged zavegepant in feces and urine, respectively.Specific PopulationsPatients with Hepatic ImpairmentIn dedicated clinical study comparing the pharmacokinetics of zavegepant in subjects with moderate hepatic impairment (Child-Pugh B) to that of normal subjects (matched healthy controls), zavegepant Cmax was 16% higher and AUC was 1.9-fold higher in patients with moderate hepatic impairment. These changes in exposures are not expected to be clinically significant, based on clinical safety experience and minimal accumulation of drug exposures. The impact of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of zavegepant was not studied [see Use in Specific Populations (8.6)]. Patients with Renal ImpairmentThe renal route plays minor role in the clearance of zavegepant. No clinically significant effect on the pharmacokinetics of zavegepant is expected in subjects with estimated creatinine clearance (CLcr) 30 mL/min or greater. In patients with CLcr 15 to 29 mL/min, accumulation of uremic solutes can cause an increase in zavegepant exposures by inhibiting OATP transporters. Zavegepant has not been studied in patients with CLcr less than 15 mL/min [see Use in Specific Populations (8.7)].Other Specific PopulationsAge, sex, race, ethnicity, and body weight did not show clinically significant effects on the pharmacokinetics of zavegepant. Drug Interaction StudiesIn Vitro StudiesEnzymes Zavegepant is substrate of CYP3A4 and to lesser extent CYP2D6. Zavegepant is not an inducer of CYP1A2, 2B6, or 3A4, or an inhibitor of CYP1A2, CYP2C9, 2C19, 2B6, 2D6, 2C8, and 3A4 at clinically relevant concentrations.Transporters Zavegepant is substrate for OATP1B3 and NTCP (see In Vivo studies).Zavegepant is also substrate for the transporters P-gp, MATE1, and MATE2-K. Considering the minor contribution of the renal pathway in the clearance of zavegepant, coadministration of zavegepant with inhibitors of P-gp, MATE1, and MATE2-K inhibitors is not expected to result in clinically significant effect on zavegepant pharmacokinetics. Zavegepant is not substrate for BCRP, OATP1B1, OAT1, OAT3, OCT2, BSEP, MRP2, MRP3, and MRP4. Zavegepant is an inhibitor of OCT2, MATE1, and MATE2-K, but drug interactions for ZAVZPRET are not expected at clinically relevant concentrations. Zavegepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, OATP1B1, and OATP1B3. In Vivo StudiesCYP3A4 Inhibitors Concomitant administration of single dose of 10 mg ZAVZPRET with itraconazole (a strong CYP3A4 and P-gp inhibitor), at steady state did not result in clinically relevant effect on the exposures of zavegepant. OATP1B3 or NTCP InhibitorsConcomitant administration of single oral dose of 100 mg zavegepant with rifampin (an OATP1B3, NTCP inhibitor and strong CYP3A inducer), at steady state resulted in increased zavegepant exposure (AUC by 2.3-fold and Cmax by 2.2-fold). The observed change in zavegepant exposures is composite effect of inhibition of OATP1B3 and NTCP transporters as well as induction of CYP3A enzymes. Concomitant administration of ZAVZPRET with inhibitors of OATP1B3 or NTCP transporters may result in significant increase in zavegepant exposure [see Drug Interactions (7.1)].OATP1B3 or NTCP Inducers Concomitant administration of ZAVZPRET with inducers of OATP1B3 or NTCP transporters has not been studied. However, since zavegepant is substrate of OATP1B3 and NTCP, concomitant administration with inducers of these transporters may result in decreased zavegepant exposure [see Drug Interactions (7.2)]. Intranasal DecongestantsThe effect of concomitant intranasal decongestants on the pharmacokinetics of zavegepant nasal spray has not been evaluated. Concomitant administration of intranasal decongestants may decrease the systemic exposure of zavegepant and potentially the efficacy of zavegepant [see Drug Interactions (7.3)]. Other DrugsNo significant pharmacokinetic interactions were observed when zavegepant was concomitantly administered with oral contraceptives (ethinyl estradiol) or sumatriptan [see Clinical Pharmacology (12.2)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of ZAVZPRET in pregnant women. No adverse developmental effects were observed following subcutaneous administration of zavegepant to pregnant animals at doses associated with plasma exposures higher than those used clinically (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPublished data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.DataAnimal DataSubcutaneous administration of zavegepant to pregnant rats (0, 10, 20, or 40 mg/kg/day) or rabbits (0, 20, 40, or 60 mg/kg/day) during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposures (AUC) at the highest doses tested were approximately 4000 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day. Subcutaneous administration of zavegepant (0, 5, 10, or 20 mg/kg/day) to rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. Plasma exposure (AUC) at the highest dose tested was approximately 2500 times that in humans at the MRHD.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert This Patient Information has been approved by the US. Food and Drug Administration3/2023PATIENT INFORMATION ZAVZPRET(TM) (zav-spret)(zavegepant)nasal sprayWhat is ZAVZPRETZAVZPRET is prescription medicine used in adults for the acute treatment of migraine attacks with or without aura.ZAVZPRET is not used to prevent migraine attacks.It is not known if ZAVZPRET is safe and effective in children.Do not use ZAVZPRET if you are:oallergic to zavegepant, or any of the ingredients in ZAVZPRET.See the end of this leaflet for complete list of ingredients in ZAVZPRET.Before you use ZAVZPRET, tell your healthcare provider about all of your medical conditions, including if you: ohave kidney problems.ohave liver problems.oare pregnant or plan to become pregnant. It is not known if ZAVZPRET will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known whether ZAVZPRET passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you use ZAVZPRET. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use ZAVZPRET oUse ZAVZPRET exactly how your healthcare provider tells you to use it.oSee the Instructions for Use for complete information on how to use ZAVZPRET nasal spray.oZAVZPRET is given in the nose (nasal) only.oEach ZAVZPRET only sprays time and cannot be reused. Do not test or prime the nasal spray before use.oEach dose of ZAVZPRET is provided in an individual pack. Use all of the medicine in pack for complete dose.oThe recommended dose is 10 mg given as single spray in one nostril.oDo not use more than spray (10 mg) of ZAVZPRET nasal spray in 24-hour period.oIt is not known if it is safe to use more than sprays (doses) of ZAVZPRET in 30 days.oAvoid using intranasal decongestants with ZAVZPRET. If you have to use an intranasal decongestant, use it at least hour after using ZAVZPRET.What are the possible side effects of ZAVZPRET ZAVZPRET may cause serious side effects including:oAllergic reactions. Allergic reactions, including hives and swelling of the face, can happen after you use ZAVZPRET. Call your healthcare provider or get emergency help right away if you have any of the following symptoms, which may be part of an allergic reaction:oswelling of the face, mouth, tongue, or throatotrouble breathing The most common side effects of ZAVZPRET are:ounusual tasteonausea onasal discomfortovomitingThese are not the only possible side effects of ZAVZPRET. Call your doctor for medical advice about side effects. You may report side effects to FDA at 800-FDA-1088.How should store ZAVZPRET oStore ZAVZPRET in the blister package that it comes in.oStore ZAVZPRET at room temperature between 68F to 77F (20C to 25C). oDo not freeze.Keep ZAVZPRET and all medicines out of the reach of children.General information about the safe and effective use of ZAVZPRET: Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ZAVZPRET for condition for which it was not prescribed. Do not give ZAVZPRET to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ZAVZPRET that is written for health professionals.What are the ingredients in ZAVZPRETActive ingredients in ZAVZPRET: zavegepantInactive ingredients in ZAVZPRET: dextrose, hydrochloric acid, sodium hydroxide, and succinic acid in water for injection. For more information, go to www.zavzpret.com or call 1-800-438-1985.LAB-1545-1.0. oallergic to zavegepant, or any of the ingredients in ZAVZPRET.. ohave kidney problems.. ohave liver problems.. oare pregnant or plan to become pregnant. It is not known if ZAVZPRET will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known whether ZAVZPRET passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you use ZAVZPRET. oUse ZAVZPRET exactly how your healthcare provider tells you to use it.. oSee the Instructions for Use for complete information on how to use ZAVZPRET nasal spray.. oZAVZPRET is given in the nose (nasal) only.. oEach ZAVZPRET only sprays time and cannot be reused. Do not test or prime the nasal spray before use.. oEach dose of ZAVZPRET is provided in an individual pack. Use all of the medicine in pack for complete dose.. oThe recommended dose is 10 mg given as single spray in one nostril.. oDo not use more than spray (10 mg) of ZAVZPRET nasal spray in 24-hour period.. oIt is not known if it is safe to use more than sprays (doses) of ZAVZPRET in 30 days.. oAvoid using intranasal decongestants with ZAVZPRET. If you have to use an intranasal decongestant, use it at least hour after using ZAVZPRET.. oAllergic reactions. Allergic reactions, including hives and swelling of the face, can happen after you use ZAVZPRET. Call your healthcare provider or get emergency help right away if you have any of the following symptoms, which may be part of an allergic reaction:oswelling of the face, mouth, tongue, or throatotrouble breathing oswelling of the face, mouth, tongue, or throat. otrouble breathing. ounusual taste. onausea onasal discomfort. ovomiting. oStore ZAVZPRET in the blister package that it comes in.. oStore ZAVZPRET at room temperature between 68F to 77F (20C to 25C). oDo not freeze.. Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oAvoid use in patients with severe hepatic impairment. (8.6)oAvoid use in patients with CLcr 30 mL/min. (8.7). oAvoid use in patients with severe hepatic impairment. (8.6). oAvoid use in patients with CLcr 30 mL/min. (8.7). 8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of ZAVZPRET in pregnant women. No adverse developmental effects were observed following subcutaneous administration of zavegepant to pregnant animals at doses associated with plasma exposures higher than those used clinically (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPublished data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.DataAnimal DataSubcutaneous administration of zavegepant to pregnant rats (0, 10, 20, or 40 mg/kg/day) or rabbits (0, 20, 40, or 60 mg/kg/day) during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposures (AUC) at the highest doses tested were approximately 4000 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day. Subcutaneous administration of zavegepant (0, 5, 10, or 20 mg/kg/day) to rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. Plasma exposure (AUC) at the highest dose tested was approximately 2500 times that in humans at the MRHD.. 8.2Lactation. There are no data on the presence of zavegepant or its metabolites in human milk, the effects of zavegepant on the breastfed infant, or the effects of zavegepant on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ZAVZPRET and any potential adverse effects on the breastfed infant from ZAVZPRET or from the underlying maternal condition.. 8.4Pediatric Use. Safety and effectiveness in pediatric patients have not been established. 8.5Geriatric Use. Clinical studies of ZAVZPRET did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.In limited number of patients 65 years of age and older, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects.. 8.6Hepatic Impairment No dosage adjustment of ZAVZPRET is necessary in patients with mild hepatic impairment (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). ZAVZPRET has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of ZAVZPRET in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].. 8.7Renal Impairment No dosage adjustment of ZAVZPRET is necessary in patients with estimated creatine clearance (CLcr) 30 mL/min or greater. Avoid use of ZAVZPRET in patients with CLcr less than 30 mL/min [see Clinical Pharmacology (12.3)].